HIV & HSC
They haven’t managed to kill me with exams yet; however, it’s not from lack of trying. But I found something so interesting yesterday that I just couldn’t keep myself from blogging about it. And by interesting, I mean terrifying. I tend to find life beautiful. Even if it is something most people would find gross, or disturbing, or horrible. I’m a biologist, it’s a documented weakness of our ilk. So when I say that the following engenders in me a feeling of profound wrongness and almost disgust, I want you to take my full meaning.
- HIV comes in two flavors, CCR5 tropic and CXCR4 tropic. You might remember a post on CCR5 tropic HIV from a while back. It basically denotes which co-receptor is necessary for the virus to enter a cell (and yes, there are dual-tropic strains). We generally focus on CCR5 because, for reasons that are not entirely clear, initial infection with HIV is almost entirely CCR5 tropic with the infection shifting to CXCR4 tropic as it progresses.
- Hematopoietic stem cells (HSC) are the source of all of your blood. ALL of your blood, myeloid and lymphoid. They are a self-renewing pool of multipotent cells, which means that they can be used to make new blood as needed (this is why you can donate blood and bone marrow have it regenerate). Among the offspring of the lymphoid lineage are the T-cells that HIV usually attacks.
Got all that? Good. Sit down. Are you sitting comfortably?
In sum, we have shown that multipotent HSPCs and HSCs can be infected by HIV and that this infection is primarily accomplished by CXCR4-tropic HIVs. The infection and destruction of multipotent HSPCs may contribute to the more rapid decline in CD4 counts associated with CXCR4-tropic HIV isolate emergence. Alternatively, as infected HSCs could create an extremely long-lived reservoir of virus, preferential infection of these cells by CXCR4-tropic virus could provide a reservoir for the emergence of CXCR4-tropic isolates late in disease: as other viral reservoirs are depleted, CXCR4-tropic virus from the HSC and HSPC reservoir could begin to predominate. In addition, our demonstration that HIV can infect cells capable of stably engrafting for months in the xenograft model indicates that HIV can infect HSCs that are capable of self-renewal and, if the integrated viral genome is latent, that it can be maintained and even expanded by cell division.
The above quote comes from an article published in this month’s Cell: Host & Microbe, and I have to say that their work looks pretty solid (at least to my exam addled brain). They performed a series of experiments using viruses generated from a minimal HIV genome and expressing three variant (R5, R4, or dual) envelope proteins. With this they demonstrated that not only could CXCR4 tropic and dual tropic viruses infect hematopoeitic progenitor cells in general, but that they could specifically do so to cells capable of multilineage reconstitution in immunocomrpmised mice. Or to put it another way: XR4 and dual tropic HIV infects HSC.
Now active HIV infection appears to kill HSC cells outright, and HSC death is really bad, but if you have been following closely you’ll realize that that isn’t the biggest worry here. Latent infection of HSC could lead to a near impossible to purge, continually renewing reservoir of infection, moreover it appears that it is possible for infected HSC to differentiate and produce daughter cells that are already infected. This means that in advanced cases of HIV infection, we might need to start looking for integrated provirus in cells that HIV technically can’t infect.
This is a blow struck to the heart of our immune system. Sure, there are genetic disorders that screw with HSC, cancers even, but a pathogen? I feel like they are breaking the rule about fighting on holy ground. It is still important to see if wild-type HIV is capable of latently infecting HSC instead of killing them outright, but given the versatility of this virus, it wouldn’t surprise me, and if that is the case it is all the more reason to lock down HIV infection as early as possible. We are really close to finding a way to flush latent infection from T-cells, and it would be a serious blow if we succeed in that only to find that HIV has yet another reservoir lying in wait.
(And okay, I admit that my disgust is laced with a teensy bit of: Oh wow that is so awesome.)
Notes & Sources
- HIV-1 Utilizes the CXCR4 Chemokine Receptor to Infect Multipotent Hematopoietic Stem and Progenitor Cells (Carter, et al. 2011)
- Thats only the second Highlander joke in three months of science blogging. I am falling behind schedule.